All-Star shortstop Reyes was put on the 15-day disabled list with a strained left hamstring and Murphy was ruled out for the season with a sprained medial collateral ligament in the left knee, the Mets said.
Both were injured in Sunday's loss to the Atlanta Braves.
Four-times All Star Reyes, who was batting .336, was injured while running to first base. He missed 12 games last month with the same injury.
Murphy, also a .300 hitter, was hurt while playing second base when Atlanta's Jose Constanza slid into his leg while attempting to steal in the seventh inning. He missed all of last season with injuries to his right knee.
The Mets (56-57), who are third in the National League East 17-and-a-half games behind Philadelphia, have had numerous injuries this season.
(Reporting by Gene Cherry in Raleigh, North Carolina; Editing by Peter Rutherford)